Composition and method for treating hyperproliferative diseases

Abstract

The present invention is directed to methods and compositions for treatment of hyperproliferative diseases. The composition of the invention comprises a carbohydrate having a backbone comprising polygalacturonan and a ligand of peripheral benzodiazepine receptor. The present compositions and methods are used to treat various cancers and other diseases where cells undergo pathological and unwanted proliferation.

1 . A method for treating cancer and unwanted proliferation of cells in a patient, said therapeutic treatment comprising the conjoint administration to said patient of a therapeutically effective amount of ligand of a peripheral benzodiazepine receptor and a carbohydrate having a partially demethoxylated polygalacturonan backbone.  
   
   
       2 . The method of  claim 1 , wherein said backbone comprises homogalacturonan.  
   
   
       3 . The method of  claim 1 , wherein said backbone comprises a partially demethoxylated polygalacturonic acid which is interrupted with rhamnose residues.  
   
   
       4 . The method of  claim 3 , wherein said carbohydrate further comprises neutral sugar side chains having a low degree of branching pendent from the backbone.  
   
   
       5 . The method of any of  claims 1  to  4 , wherein said ligand is selected from: 
 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquino-linecarboxamide (PK11195), 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2-H-1,4-benzodiazepin-2 (4-chlorodiazepam or Ro5-4864), porphyrins, alpidem, N-(2,5-dimethoxybenzyl)-N-5-fluoro-2-phenoxyphenyl)acetamide (DAA1106), 2-aryl-3-indoleacetamide (FGIN-1), diazepam (Valium), flumazenil (Romazicon) or lonidamine.    
   
   
       6 . The method of any of  claims 1  to  4 , further comprising a chemotherapeutic agent.  
   
   
       7 . The method of  claim 6 , wherein said chemotherapeutic is a topoisomerase inhibitor.  
   
   
       8 . The method of  claim 7 , wherein said topoisomerase inhibitor is selected from the group consisting of adriamycin, amsacrine, camptothecin, daunorubicin, dactinomycin, doxorubicin, eniposide, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide, and topotecan.  
   
   
       9 . The method of  claim 8 , wherein said inhibitor is etoposide.  
   
   
       10 . The method of  claim 1 , used in the treatment of a proliferative disorder selected from the group consisting of a pancreatic cancer, renal cell cancer, Kaposi's sarcoma, chronic leukemia, chronic lymphocytic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, lymphoma, mesothelioma mastocytoma, lung cancer, liver cancers, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, gastrointestinal cancer, stomach cancer, myeloma, prostate cancer, B-cell malignancies or metastatic cancers.  
   
   
       11 . The method of  claim 1 , used to inhibit growth of a tumor cell selected from the group consisting of a pancreatic tumor cell, a lung tumor cell, a prostate tumor cell, a breast tumor cell, a colon tumor cell, a liver tumor cell, a brain tumor cell, a kidney tumor cell, a skin tumor cell and an ovarian tumor cell.  
   
   
       12 . The method of  claim 1 , used to inhibit growth of a tumor cell selected from the group consisting of a squamous cell carcinoma, a non-squamous cell carcinoma, a glioblastoma, a sarcoma, an adenocarcinoma, a myeloma, a melanoma, a papilloma, a neuroblastoma and a leukemia cell.  
   
   
       13 . The method of  claim 1 , wherein said carbohydrate is a partially depolymerized pectin.  
   
   
       14 . The method of  claim 13 , wherein said partially depolymerized pectin comprises a pH modified pectin, an enzymatically modified pectin, or a thermally modified pectin.  
   
   
       15 . The method of  claim 13 , wherein said partially depolymerized pectin comprises a modified citrus pectin.  
   
   
       16 . The method of  claim 13 , wherein said partially depolymerized pectin has a molecular weight of 1 to 500 kilodaltons (kDa).  
   
   
       17 . The method of  claim 13  wherein said partially depolymerized pectin has a molecular weight of 10 to 250 kDa.  
   
   
       18 . The method of  claim 13  wherein said partially depolymerized pectin has a molecular weight of 50 to 200 kDa.  
   
   
       19 . The method of  claim 13  wherein said partially depolymerized pectin has a molecular weight of 70 to 150 kDa.  
   
   
       20 . The method of  claim 13  wherein said partially depolymerized pectin has a molecular weight of 80 to 100 kDa.  
   
   
       21 . The method of  claim 13 , wherein said partially depolymerized pectin is administered by intravenous infusion.  
   
   
       22 . The method of  claim 13 , wherein said partially depolymerized pectin is administered orally.  
   
   
       23 . The method of  claim 13 , wherein said partially depolymerized pectin is administered by intramuscular or intraperitoneal injection or infusion.  
   
   
       24 . The method of  claim 13 , wherein said partially depolymerized pectin is administered by inhalation.  
   
   
       25 . The method of  claim 13 , wherein said partially depolymerized pectin is administered by topically.  
   
   
       26 . The method of  claim 13 , wherein said partially depolymerized pectin is administered by subcutaneous injection.  
   
   
       27 . A kit comprising (i) a ligand of peripheral benzodiazepine receptor, (ii) a therapeutically effective amount of a carbohydrate having a galacturonan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone; and (iii) instructions and/or a label for conjoint administration of the ligand and the carbohydrate.